This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study will observe subjects with Rheumatoid Arthritis and their families who may have an increased risk for developing the same or other autoimmune diseases. Hopefully this will increase our understanding of the immunopathogenesis of RA. We believe that this first step toward defining the relationship between genetic risk, epidemiologic exposures and RA related autoimmunity in clinically unaffected individuals is important to increasing our current understanding of the immunopathogenesis of RA. In addition, this study can help to lay the groundwork for the performance of prospective studies in sub-groups of asymptomatic individuals at especially high risk for developing RA. Both types of studies are essential to our long term goal of developing strategies for the selection of clinically unaffected individuals who carry high risk HLA alleles and exhibit RA related autoantibodies that would be candidates for prevention strategies or very early therapeutic interventions. In this regard, although such a strategy in RA, or indeed any autoimmune disease, may be thought to be impractical, extensive experience at the University of Colorado Health Sciences Center and elsewhere in Type 1 DM has demonstrated that this approach is rational and has substantial scientific relevance as well as therapeutic potential. In one particular study in Denver, termed DAISY (Diabetes and Autoimmunity Study in the Young) children at high risk for the development of Type 1 DM as defined by the presence of disease-associated DR4 and DR3 HLA alleles have been identified during a population screen of >25,000 newborns and then enrolled into a prospectively followed cohort with a current duration of up to ten years. These children and those from other cohort composed of healthy FDRs of individuals affected with Type 1 DM are being followed prospectively for the development of islet-specific autoimmunity. Relevant to our long-term goals, children in Denver and elsewhere who develop highly predictive Type 1 DM related autoantibodies have already been randomized into prevention trials prior to the development of clinically apparent disease. Although the prevention strategies were not successful, the demonstration that a population at risk could be identified and undergo a clinical trial has led to substantial interest in developing new ways to treat this and other autoimmune disease in the auto antibody positive but clinically asymptomatic period. The long-term goal of the study is to identify, during the pre-clinical phase of disease, those healthy individuals who are at sufficiently high risk for developing Rheumatoid Arthritis (RA) so that a rational primary prevention strategy can be employed. Our first objective will be to determine if RA-related autoantibodies are present in healthy subjects. Secondly, we will follow those subjects with autoantibodies prospectively in order to determine if they predict the future development of RA. Finally, we will screen for environmental factors which may be associated with the appearance of RA-related autoantibodies. Since the screening tests for these autoantibodies have been recently developed and tested only in patients with known RA, their clinical relevance in a healthy population has not yet been determined.